This invention relates to substituted benzamides corresponding to the general formula I ##STR2## and their use in medicaments.
Autoimmune diseases arise as a result of a reaction of the immune system against endogenous structures. In the course of this the normally present tolerance towards endogenous tissues is suspended. Antibodies, and in particular T-lymphocytes and monocytes/macrophages, play an important part in the pathogenesis of the various autoimmune diseases. Activated monocytes/macrophages secrete a multitude of different inflammatory intermediaries, which are directly or indirectly responsible for the breakdown of the tissues affected by the autoimmune disease. The activation of the monocytes/macrophages is mediated either by the interaction with T-lymphocytes or by bacterial products such as lipopolysaccharide (LPS). The activation of monocytes/macrophages and of granulocytes induced by various bacterial products is moreover characteristic of inflammatory reactions in general.
The importance of the equilibrium between inflammatory (for example, interleukin IL-12) and anti-inflammatory cytokines (for example, interleukin IL-10) for the development and progress of inflammation and autoimmune diseases is clearly documented because of numerous experiments on animals and initial clinical trials. The pathophysiological significance of IL-12 is apparent in various animal models for diseases such as rheumatoid arthritis, multiple sclerosis, diabetes mellitus, as well as inflammatory diseases of the skin and mucous membranes (Immunol. Today 16/8: 383-387, 1995; J. Immunol. 155: 4661-4668, 1995; J. Exp. Med. 182: 1281-1290, 1995; J. Exp. Med. 187/4: 537-546, 1998). The respective diseases were triggered by the application of IL-12 and an abatement of the course of the disease, extending to a recovery of the animals, was apparent after neutralisation of endogenous IL-12.
In inflammatory bowel diseases, both in diseased animals and in patients suffering from Crohn's disease, there is a distinctly increased T-cell reactivity in the inflamed sections of the gut. This T-cell reactivity is characterised by the increased expression of IL-12 and IFN- in the lesions. On the other hand, the immunosuppressive cytokine IL-10 is clearly diminished in the lesions (Immunity 3: 171-174, 1995; J. Exp. Med. 182: 1281-1290, 1995; Eur. J. Immunol. 26: 1156-1163; Eur. J. Immunol. 28: 379-389, 1998). The importance of the immunosuppressive cytokine IL-10 for the development of inflammatory intestinal diseases is also apparent from the fact that IL-10 knockout mice develop a spontaneous colitis (Immunity 3: 171-174, 1995). The activation of the IFN-y-producing T-cells in the lamina propria of the intestine depends substantially on the local formation of IL-12. Antibodies to IL-2 abrogate established experimental colitis in mice. The neutralization of IL-12 by antibodies led to a striking improvement in both the clinical and histopathological aspects of the disease within a few days. No IFN-.gamma. production could be detected in in vitro activated T-cells from the lamina propria of mice which received anti-IL-12 treatment (J. Exp. Med. 182: 1281-1290).
Application of recombinant IL-10 in humans confirms the anti-inflammatory properties. Following the administration of IL-10 to healthy subjects, the formation of the inflammatory cytokines TNF-.alpha. and IL-1 by monocytes activated ex vivo with LPS is reduced by 65 to 95% (J. Immunol. 154: 5492-5499, 1995). The use of IL-10 in patients suffering from steroid-refractory Crohn's disease resulted in an improvement in the clinical symptoms (Gastroenterology, 113: 383-389). Recently, the subcutaneous application of IL-10 to three patients suffering from psoriasis was also reported. There was a marked improvement in the symptoms of the disease. Moreover, the formation of IL-12 and TNF as well as the expression of surface molecules on monocytes were also decreased (J. Clin. Invest. 101: 783-794). The use of antibodies against IL-12 in humans is now imminent.
In summary, it can be stated that a deficiency of IL-10 or an excess of IL-12 determines the pathophysiology of a multitude of inflammatory diseases. Attempts to normalize the IL-10/IL-12 balance therefore have a great therapeutic potential.